G-quadruplexes (G4s) are nucleic secondary structures characterized by G-tetrads. G4 motif stabilization induces DNA damage and cancer cell death; therefore, G4-targeting small molecules are the focus of clinical investigation. DNA destabilization induced by G4 ligands might potentiate the anticancer activity of agents targeting DNA or inhibiting its repair such as oncolytic viruses. This study represents the first approach combining G4 ligands, BRACO-19 (B19), pyridostatin (PDS), and the adenovirus dl922-947 in breast cancer cells. We demonstrated that G4 binders and dl922-947 induce cytotoxicity in breast cancer cells (MDA-MB-231 and MCF-7) and at higher doses in other neoplastic cell lines of thyroid (BHT-101 cells) and prostate (PC3 cells). G4 binders induce G4 motifs distributed in the S and G2/M phases in MCF-7 cells. G4 binder/dl922-947 combination increases cell cytotoxicity and the accumulation in subG0/G1. Indeed, G4 binders favor viral entry and replication with no effect on coxsackie and adenovirus receptor. Notably, dl922-947 induces G4 motifs and its combination with PDS potentiates this effect in MCF-7 cells. The agents alone or in combination similarly enhanced cell senescence. Additionally, PDS/dl922-947 combination inactivates STING signaling in MDA-MB-231 cells. Our results suggest that G4 binder/virotherapy combination may represent a novel therapeutic anticancer approach.

The growing interconnections between people, markets and networks together with the development of new technologies have increased the frequency and impact of large-scale disasters around the globe. Many of these events, defined as emerging catastrophic (or systemic) risks, have no previous record. At the same time there is a strong probability that their frequency and impact will increase in the future. This paper takes a governance perspective by assuming that policy actions should be designed to cope with ignorance and large-scale losses, being the primary features characterising such emerging catastrophic risks. Precisely, the governance activity should aim both at expanding the industries' capacity to absorb losses and at acquiring more information about frequency and impact of such losses. However, it appears that some solutions may conflict with policy objectives. In particular, direct governmental interventions to compensate victims and stringent antitrust policy goals might block the development of a market for first-party property insurance for emerging systemic risks. This paper elicits crucial points that require further elaboration by policy-makers, thereby stressing the importance of providing a workable legal definition of such line of risk that embraces the precautionary principle.

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